Diabetes affects more than 8% of Americans with an annual cost of over $245 billion in USA. Although medical therapies are available, there are diabetic patients who are refractory to medical therapies or cannot be treated medically due to side effects such as weight gain and hypoglycemia. Vagal nerve stimulation (VNS) has been applied or under investigation for treating epilepsy, therapy- resistance depression, obesity and heart failure due to its inhibitory or excitatory effect on autonomic functions. In this project, we propose to apply VNS to treat diabetes and further we propose to apply VNS only during the postprandial periods. The novel concept of VNS for glycemic control is based on the facts that autonomic imbalance is common in diabetes and VNS is capable of improving autonomic imbalance. A hypoglycemic effect has been observed with VNS of appropriate parameters in our preliminary studies and further VNS has been shown to increase glucagon-like peptide-1 and inhibit plasma ghrelin. The specific aims of this project are 1) to derive a most effective method of VNS in reducing blood glucose in a canine model of diabetes by systematically optimizing VNS parameters, location and duration; 2) to investigate the effects of the optimized VNS on gastrointestinal motility and hormones; 3) to investigate the chronic effects of VNS on glycemic control and its safety profile. The implantable pulse generator from CVRx will be used to explore the therapeutic potential of VNS for diabetes. The novelties of this project include: 1) a novel application of VNS for diabetes; VNS has been applied for treating obesity but little was reported for diabetes. Low frequency VNS will be used for improving autonomic imbalance and gastrointestinal dysmotility therefore reducing blood glucose 2) VNS will be delivered only during food intake which prevents tachyphylaxis; 3) a novel concept of treating obesity by improving autonomic functions; 4) The involvement of incretin hormones with VNS is new. A competitive team has been assembled to include expertise in neuromodulation, gastrointestinal motility, clinical management on diabetes, medical device and software development.